Benjamin Caballero

Psychobiological effects of carbohydrate- and protein-rich meals in patients with seasonal affective disorder and normal controls

Patients with seasonal affective disorder (SAD) frequently report carbohydrate craving and note that carbohydrate ingestion energizes them. Bright artificial light has been shown to reverse the symptoms of SAD, including carbohydrate craving. In this study, 16 depressed SAD patients and 16 matched controls were fed two different isocaloric meals, one rich in protein and one rich in carbohydrates, in a crossover design. Although their biochemical response in terms of plasma large neutral amino acid concentrations was identical, SAD patients reported activation following carbohydrate ingestion, whereas normal controls reported sedation. Marked ordering effects on psychological parameters were noted, suggesting that order should be taken into account as a methodological consideration in meal studies.

Plasma amino acids and insulin levels in obesity: Response to carbohydrate intake and tryptophan supplements

We assessed the plasma amino acids, glucose, and insulin responses of obese and lean control subjects to midafternoon carbohydrate snacks. After a standard 400 kcal lunch, eight lean and nine obese subjects received, at 2PM, a 30 g sucrose snack; blood samples were obtained at hourly intervals until 6 PM. Each subject participated in four similar studies in which the carbohydrate snack was consumed alone or with 250, 500, or 1,000 mg of L-tryptophan (Trp), offered as a capsule. The obese group exhibited elevated plasma levels of the branched-chain amino acids, phenylalanine and tyrosine, and the levels of these amino acids declined much less in response to carbohydrate intake than in lean controls. As a consequence, the plasma ratio of Trp:large neutral amino acids (Trp/LNAA ratio), which normally rises after carbohydrate consumption, showed virtually no change in the obese group. The plasma Trp/LNAA response of this group did not reach control values even when carbohydrate intake was increased to 50 or 75 g. Peak plasma Trp concentrations and Trp/LNAA ratios after 250, 500, and 1,000 mg Trp doses were also significantly lower in the obese. Since brain Trp uptake is strongly correlated with the plasma Trp/LNAA ratio, which in turn determines the rate of brain serotonin synthesis, the blunted Trp/LNAA response to carbohydrate intake in the obese could contribute to alterations in the serotonin-mediated regulation of food intake.

Differential effects of insulin resistance on leucine and glucose kinetics in obesity

The effects of insulin resistance on glucose and amino acid metabolism were studied in obese nondiabetic women (body mass index [BMI], (32.8 +/- 2) and in lean controls. Glucose disposal rate, hepatic glucose production, and leucine carbon flux and oxidation were simultaneously measured during the postabsorptive state and during euglycemic hyperinsulinemia, by means of primed, constant infusions of D-[6,6-2H2]glucose and L-[1-13C]leucine. Each subject participated in two insulin clamp studies on separate days, at infusion rates of 10 and 40 mU (m2.min)-1, producing plasma insulin levels of 20 to 25 and 70 to 80 microU/mL, respectively. Fat-free mass (FFM) was calculated from underwater weighing measurements. Insulin-mediated glucose disposal rate was significantly slower in the obese group: 2.05 +/- 0.05 versus 3.84 +/- 0.18 mg (kg.min)-1 in controls during the 10-mU insulin clamp, and 3.80 +/- 0.23 versus 9.16 +/- 0.47 mg (kg.min)-1 during the 40-mU clamp. The insulin-induced decrease in plasma levels of branched chain amino acids was also significantly blunted in the obese group. Baseline leucine flux was similar in lean and obese subjects (78 +/- 3 and 71 +/- 2 mumol (kg.h)-1, respectively), and its decline in response to insulin infusion was also comparable (8% and 10% during the 10-mU/m2 clamp, and of 17% and 18% during the 40-mU/m2 clamp in lean and obese, respectively). Basal leucine carbon oxidation (from [13C]leucine and [13C]alpha ketoisocaproate [alpha-KIC] plasma enrichments) was also similar in lean and obese, and did not change significantly with insulin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

A balanced carbohydrate protein diet in the management of Parkinson's disease

Although restricting dietary protein is a proposed adjunct to treating Parkinsons disease (PD), the effect of carbohydrate consumption is unknown. We measured plasma levodopa and large neutral amino acid (LNAA) levels in nine PD patients treated with carbidopa/levodopa and different isocaloric meals containing high protein-low carbohydrate, low protein-high carbohydrate, and balanced 5:1 carbohydrate:protein mixtures. We found that levodopa levels increased significantly regardless of the type of diet, but that plasma LNAA levels varied less and motor performance was superior after the balanced diet than after the other two meals. We conclude that PD patients can consume nutritionally adequate meals and still maintain a stable plasma levodopa: LNAA ratio.

Mineral homeostasis in obesity: Effects of euglycemic hyperinsulinemia

We explored the effects of insulin on mineral homeostasis in five lean and six moderately obese nondiabetic premenopausal women. Serum and urine minerals were measured before and during the steady-state phase of a euglycemic insulin clamp. Each subject participated in two insulin clamp studies on separate days at insulin infusion rates of 10 and 40 mU/m2/min. Euglycemic hyperinsulinemia was associated with (1) a significant increase in urinary calcium excretion when expressed per minute with no change in total serum calcium; (2) a decrease in urine and serum phosphate; (3) a decrease in serum potassium with no change in urine potassium; and (4) no measurable effects on urine or serum sodium. At any given insulin level, the obese individuals excreted significantly more calcium, phosphate, and potassium per minute than lean controls. While insulin administration had no effect on serum parathyroid hormone (PTH) or vitamin D levels, baseline serum 1,25(OH)2D concentration was significantly higher and serum ultrafilterable calcium was significantly lower in obese subjects than in lean controls.

The Composition of Lunch Determines Afternoon Plasma Tryptophan Ratios in Humans

It is well established that the ratio of the plasma tryptophan concentration to those of the other large neutral ammo acids determines the transport of tryptophan into the brain. Brain tryptophan levels, in turn, control production of the neurotransmitter serotonin. Protein-rich meals, when consumed in the morning after an overnight fast, have been shown to decrease the plasma tryptophan ratio, while carbohydrate-rich meals have the opposite effect. We now show that these meals have similar effects when consumed for lunch, even if they are preceded by a small breakfast meal.

Plasma amino acid levels after single-dose aspartame consumption in phenylketonuria, mild hyperphenylalaninemia, and heterozygous state for phenylketonuria

Aspartame (N-aspartyl-phenylalanine methyl ester), a widely used artificial sweetener, is hydrolyzed in the intestinal lumen to methanol and to its constituent amino acids phenylalanine and aspartic acid. Ingestion of this sweetener causes a sharp increase in plasma phenylalanine levels in normal persons a and in patients with phenylketonuria? The label on aspartame-containing products includes a warning to patients with PKU, but no information on the actual sweetener content, and there is concern that aspartame ingestion by those who do not have PKU could produce phenylalanine levels sufficiently high to harm the brain, especially among the estimated 2% of the general population who carry the gene for PKU and thus have a reduced capacity for phenylalanine metabolism. Studies in rats show that elevations of plasma phenytalanine levels, as

The Effects of Aspartame on Human Mood, Performance, and Plasma Amino Acid Levels

Consumption of the artificial sweetener aspartame raises plasma phenylalanine levels, thereby increasing brain phenylalanine and, conceivably, affecting the syntheses of monoaminergic brain neurotransmitters known to underlie various types of behavior. We have thus assessed the effects of single aspartame doses on certain types of behavior, particularly those relating to mood and performance. In a double-blind, placebo-controlled, crossover study, a single dose of aspartame (60 mg/kg), or the same dose in combination with 37 g of carbohydrate, was administered to 20 male volunteers. [Carbohydrates enhance the entry of circulating phenylalanine into the brain by lowering plasma levels of competing large neutral amino acids (LNAA)]. A lower dose of aspartame (20 mg/kg) was also tested. Aspartame alone, or in combination with carbohydrate, did not alter any aspect of behavior that we assessed, nor did it produce detectable side effects. The ratios of plasma phenylalanine and tyrosine concentrations to those of the other LNAA were significantly increased by administration of aspartame. Since anecdotal reports of aspartame-associated neurological or behavioral side effects almost always describe effects as occurring after multiple aspartame exposures, it would be important to repeat our study using a protocol involving repeated aspartame administration.

Control of Plasma Phenylalanine Levels

Virtually all of the molecules of the essential amino acids that enter the body derive from dietary proteins; high-quality protein sources such as eggs or milk provide around 5 g of phenylalanine (Phe) per 100 g of protein. A large fraction of dietary Phe is hydroxylated to tyrosine in the liver, a process catalyzed by the enzyme Phe-hydroxylase. Plasma Phe levels, like those of the other amino acids, are not regulated, and at any given time they reflect the proportions of protein and carbohydrates in the meal most recently consumed. Since people eat during the daytime, there is an apparent circadian rhythmicity in plasma amino acid concentrations. Protein consumption tends to decrease brain Phe concentrations because although it raises plasma Phe, it increases much more the level of the other neutral amino acids (e.g., valine, leucine, isoleucine, tyrosine, and tryptophan), which compete with Phe for brain uptake. In contrast, consumption of pure Phe or of aspartame increases brain Phe because of the lack of these competing amino acids. In rodents, which have a very active Phe-hydroxylating system, administration of pure Phe or aspartame causes larger increases in plasma and brain tyrosine than in Phe, unless very high doses are given. This does not occur in humans, because Phe hydroxylation is much slower.

Insulin Resistance and Ammo Acid Metabolism in Obesity

The association of obesity with high plasma insulin levels has been known for over 20 years. This hyperinsulinemia appears to be a compensatory response to a decreased tissue sensitivity to insulins action on glucose metabolism in the obese, and is manifested by a decreased peripheral glucose uptake, excessive hepatic glucose production in the basal state, and inadequate suppression of hepatic glucose output by exogenous insulin.2 Most moderately obese persons have a normal oral glucose tolerance test (OGTT), but they exhibit an excessive insulin rise in response to glucose intake, consistent with the lower tissue responsiveness to insulin. Thus, obese persons may be exposed for long periods of time to abnormally high plasma insulin levels, which may, in fact, be necessary to sustain a normal glycemia; but because the responsiveness to insulin, may be different for other insulin-dependent metabolic functions, this hyperinsulinemia may be either excessive or insufficient for these processes. Systemic insulin concentration results from the balance between pancreatic Bcell production and hepatic removal, and an impairment in either one of these processes has been proposed to explain the hyperinsulinemia of obesity. Some studies found that exogenous insulin is unable to completely suppress pancreatic insulin production, as estimated by the plasma C peptide level and the C peptide: insulin molar ratio (C : I);3,4 others, however, found normal C peptide levels and a low C : I ratio in obese individual^.^^ The few studies that measured portal vein insulin concentrations directly found values similar to those in the systemic circul a t i ~ n . ~ . ~ Because these results reflect the response of a heterogeneous population of obese subjects, it is possible that overproduction or decreased removal of insulin is predominant in different types of obesity. Misbin suggested that overproduction is predominant in obese with moderate hyperinsulinemia and normal glucose tolerance, whereas decreased insulin degradation plays the principal role in those with very high plasma insulin concentrations and impaired glucose tolerance. The decreased tissue sensitivity to insulin of obesity involves receptor and postreceptor defects. Studies in obese humans and in animal models of obesity have shown a decreased number of insulin receptors in a variety of tissues: skeletal adipocyte~,~ thymic lymphocyte^,^ hepatocytesL5J6 and circulating mon~cytes. ~ Studies in humans have also demonstrated a correlation between the number of receptors in circulating monocytes and insulin sensitivity measured by the insulin clamp technique. l 8 Regional perfusion studies in obese humans show that insulin resistance is present in muscle (quantitatively the most imp~rtant) , ~ adipose tissue, liver,* and the splanchnic bed.20*21 Because under normal conditions only a small number of receptors must be active to exert insulin